Cis-Repression of Foxq1 Expression Affects Foxf2-Mediated Gene Expression in Palate Development.
Cis-Repression of Foxq1 Expression Affects Foxf2-Mediated Gene Expression in Palate Development.
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FOXQ1表达的顺式抑制会影响FOXF2介导的基因表达。
DOI：
10.3389/fcell.2021.665109
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发表时间：
2021
影响因子：
5.5
通讯作者：
Jiang R
中科院分区：
文献类型：
--
作者：
Xu J;Liu H;Lan Y;Jiang R
编码叉头家族转录因子成员的FOXF2基因的破坏与人类和小鼠的腭裂有关。FOXF2位于一个包含FOXQ1、FOXF2和FOXC1的保守基因簇中。我们发现，在Foxf2 - / - 小鼠胚胎的胚胎腭间充质中，Foxq1的表达显著上调。我们在此表明，Foxf2启动子缺失突变导致顺式连接的Foxq1等位基因表达大幅增加，但对反式的Foxq1等位基因影响很小。我们分析了Foxf2突变对其他邻近基因表达的影响，并将这些影响与染色质结构域、最近确定的增强子 - 启动子关联以及H3K27ac ChIP - seq数据进行了比较。我们表明，Foxf2突变导致与Foxf2位于同一拓扑相关结构域的Foxq1和Exoc2基因表达显著增加，但不影响位于相邻染色质结构域的Foxc1和Gmds基因的表达。我们使用CRISPR基因组编辑技术使Foxf2条件性等位基因纯合的小鼠中的Foxq1基因失活，并产生了在顺式中Foxf2和Foxq1具有功能丧失突变的(Foxf2/Foxq1)+ / - 小鼠。虽然(Foxf2/Foxq1) - / - 小鼠在出生时表现出与Foxf2 - / - 小鼠相似的腭裂，但对大量Foxf2依赖基因的系统表达分析表明，与Foxf2 - / - 胚胎相比，(Foxf2/Foxq1) - / - 胚胎在发育中的腭板上对几个重要基因（包括Foxf1、Shox2和Spon1）的结构域特异性表达表现出不同的影响。这些结果确定了Foxf2突变的一种新的顺式调控效应，并证明Foxq1的顺式调控导致了Foxf2 - / - 胚胎中腭基因表达的改变。这些结果对启动子或基因缺失等位基因研究结果和机制的解释具有重要意义。此外，本研究中产生的独特小鼠品系为理解Foxf2和Foxq1基因在发育和疾病中的交叉调控和组合功能提供了宝贵资源。
Disruption of FOXF2, encoding a member of the Forkhead family transcription factors, has been associated with cleft palate in humans and mice. FOXF2 is located in a conserved gene cluster containing FOXQ1, FOXF2, and FOXC1. We found that expression of Foxq1 is dramatically upregulated in the embryonic palatal mesenchyme in Foxf2–/– mouse embryos. We show here that the Foxf2 promoter-deletion mutation caused dramatically increased expression of the cis-linked Foxq1 allele but had little effect on the Foxq1 allele in trans. We analyzed effects of the Foxf2 mutation on the expression of other neighboring genes and compared those effects with the chromatin domain structure and recently identified enhancer-promoter associations as well as H3K27ac ChIP-seq data. We show that the Foxf2 mutation resulted in significantly increased expression of the Foxq1 and Exoc2 genes located in the same topologically associated domain with Foxf2 but not the expression of the Foxc1 and Gmds genes located in the adjacent chromatin domain. We inactivated the Foxq1 gene in mice homozygous for a Foxf2 conditional allele using CRISPR genome editing and generated (Foxf2/Foxq1)+/– mice with loss-of-function mutations in Foxf2 and Foxq1 in cis. Whereas the (Foxf2/Foxq1)–/– mice exhibited cleft palate at birth similar as in the Foxf2–/– mice, systematic expression analyses of a large number of Foxf2-dependent genes revealed that the (Foxf2/Foxq1)–/– embryos exhibited distinct effects on the domain-specific expression of several important genes, including Foxf1, Shox2, and Spon1, in the developing palatal shelves compared with Foxf2–/– embryos. These results identify a novel cis-regulatory effect of the Foxf2 mutation and demonstrate that cis-regulation of Foxq1 contributed to alterations in palatal gene expression in Foxf2–/– embryos. These results have important implications for interpretation of results and mechanisms from studies of promoter- or gene-deletion alleles. In addition, the unique mouse lines generated in this study provide a valuable resource for understanding the cross-regulation and combinatorial functions of the Foxf2 and Foxq1 genes in development and disease.
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影响因子：
16
作者：
Dillon, N;Trimborn, T;Grosveld, F
通讯作者：
Grosveld, F
影响因子：
64.8
作者：
Gorkin, David U.;Barozzi, Iros;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.5
作者：
CHOI, ORB;ENGEL, JD
通讯作者：
ENGEL, JD
影响因子：
64.5
作者：
Bonev B;Mendelson Cohen N;Szabo Q;Fritsch L;Papadopoulos GL;Lubling Y;Xu X;Lv X;Hugnot JP;Tanay A;Cavalli G
通讯作者：
Cavalli G
影响因子：
--
作者：
Lan Y;Xu J;Jiang R
通讯作者：
Jiang R